Cross-Cultural Translation into Brazilian Portuguese and Validation of the Oral Anticoagulation Knowledge Tool (AKT-Br)

Introduction Oral anticoagulants are the treatment of choice for diverse types of coagulation disorders. Warfarin is widely used by the Brazilian population, possibly due to its lower cost than other oral anticoagulants. However, it has a high risk of serious adverse effects if used incorrectly. The Anticoagulation Knowledge Tool (AKT) can assess a patient’s knowledge about her/his oral anticoagulant therapy and can assist health professionals in identifying patients with difficulties in adherence. This study aimed to translate, culturally adapt, and validate the AKT into Brazilian Portuguese. Methods After a standard forward-backward procedure to translate the AKT into Brazilian Portuguese (AKT-Br), a version of the instrument was applied in three groups (patients, pharmacists, and the general population). The reliability of the AKT-Br was tested using an internal consistency measure and test-retest. The validity of the instrument was confirmed with data from the contrasted groups. All statistical analyses were performed with RStudio. Results The median scores obtained with the AKT-Br were 29.0, 17.0, and 7.5 for pharmacists, patients, and the general population, respectively (maximum score of 35 points). There was moderate internal consistency for the instrument and test-retest reliability was satisfactory. Analysis of variance for validity of the groups revealed a significant relationship between the total score and the evaluated groups. Conclusion The ATK-Br is a reliable and valid tool to assess knowledge about oral anticoagulants. AKT-Br can be used in clinical practice as an auxiliary tool to improve patient care through personalised educational interventions.


INTRODUCTION
Atrial fibrillation and deep vein thrombosis are associated with substantial morbidity and mortality worldwide, resulting in medical and economic burdens [1,2] . Patients with atrial fibrillation have a fivefold increased risk of stroke and related death compared with patients without this condition [3,4] .
Oral anticoagulant therapies (OAC), which are broadly classified into vitamin K antagonists (VKA) and direct oral anticoagulants (DOAC), are highly effective for the management of thromboembolic disorders; their use reduces the risk of stroke and systemic embolism by around two thirds [5,6] . However, these therapies are considered high-risk medications. Although VKA Brazilian Journal of Cardiovascular Surgery A direct translation from English to Portuguese was performed by two independent Portuguese mother language translators (V.F, K.S), both with previous knowledge about anticoagulation. The consensus of this stage was reached through a discussion panel involving the two translators and the key-country consultant (R.P) and the project manager (F.M). The back-translation process was performed independently by two other translators (A.F, F.T), both without previous knowledge of the AKT, leading to a literal translation of the document. The consensus of this second stage occurred through a discussion panel involving R.P and F.M that compared the back translation with the original tool to finally obtain the AKT-Br version (see Supplementary Material).
Quantitative validity of the AKT-Br was achieved through the content validity index (CVI) and followed the minimum recommendations described by Lawshe [18] and Lynn [19] . This phase involved a panel, with five anticoagulation experts, to obtain a level of agreement on the tool items. The clarity of the text, relevance, and quality of the back translation of each item were discussed. Items with a CVI < 1 were reassessed, deleted, or replaced. The clarity and relevance of the items were assessed using a four-point Likert scale (1 = not clear/not relevant; 4 = highly clear/highly relevant) and the back translation correspondence regarding the original instrument (1 = does not match; 4 = totally matches) [19] . The CVI was calculated using two approaches (item level [I-CVI] and scale level [S-CVI]), considering the average of the scores of the I-CVIs and error scale [20] . The I-CVI is the index that expresses the proportion of agreement among the evaluators for a given item and, according to Lynn [19] , in a panel of "five or fewer specialists, everyone must agree with the validity of the content for its classification to be considered a reasonable representation of the universe of possible classifications". Any result < 100% agreement (< 1) deserves due attention and possible reassessment until reaching unanimous agreement among the evaluators. The S-CVI is equivalent to the average percentage of agreement between the items and, according to Waltz et al. [21] , the recommended standard acceptability criterion is 0.90.

Assessment of Psychometric Proprieties
A cross-sectional study with convenience sampling was performed, following the protocol conducted in the original AKT [14] . The samples were obtained in a non-probabilistic manner for convenience sampling of three groups with different levels of knowledge about OAC: pharmacists (the pharmacist group), users of oral anticoagulants (the patient group), and the general population (the population group). Pharmacists were eligible to participate if they had at least one year of clinical experience or worked in community pharmacies. Patients were eligible if there were over 18 years of age and used any OAC. Eligible individuals from the general population were over 18 years old who were not receiving treatment with OAC or did not have relatives or close friends undergoing treatment with these therapies. Participants were informed of the anonymity and confidentiality of their responses. To participate in the study, participants needed to provide written informed consent. The exclusion criteria for Patients with great knowledge of their medication and clinical condition can participate in self-management, are more likely to adhere to treatment, and have a positive control of their coagulation compared with those with inadequate knowledge, in whom it is common to observe difficult coagulation control, increased risk of bleeding, and more readmissions [9][10][11][12][13] . In this context, a number of tools have been developed to assess a patient' s knowledge on OAC [14,15] , including the Anticoagulation Knowledge Tool (AKT) that covers patients who are prescribed DOAC or VKA.
The AKT measures a patient's knowledge of her/his treatment. According to the results obtained with this tool, health professionals can select other interventions for the needs of each patient, such as providing guidance on diet, possible drug interactions, and the importance of keeping the international normalized ratio (INR) in an ideal range. However, evidence regarding the AKT psychometric proprieties, validity, and reliability are unavailable in non-English speaking settings, such as for the Brazilian Portuguese population. Translation and cross-cultural validation methods allow valid translations of psychometric tools from one language to another [16,17] . Thus, we aimed to provide further evidence on the validity of the AKT and to develop the Brazilian version of this tool (AKT-Br).

AKT Description
The AKT is an instrument with evidence of validity and reliability of construct developed by Obamiro et al. [14] . It measures a patient's knowledge of her/his anticoagulant therapy through self-administered questions and calculated scores. The AKT has 28 items (open-ended and multiple-choice questions) divided into two sections (A and B) with a maximum score of 35 points and 25 points, respectively, for VKA users and DOAC users. This difference between scores is because section B of the tool is exclusive dedicated for VKA users. Section B has eight items and a maximum score of 10 points. Section A (applied to all OAC users -both VKA and DOAC) presents 20 items and has a maximum score of 25 points. This section covers general questions about anticoagulants. To each given answer, a zero (incorrect answer) or a one (correct answer) is attributed by the clinicians to assess a patient's knowledge [14] .

Cultural and Linguistic Validation
We performed a culturally acceptable translation of AKT into Brazilian Portuguese. This step followed the International Society for Pharmacoeconomics and Outcomes Research (or ISPOR) recommendations [17] ; it involved researchers to translate, back translate, apply, and validate the instrument. have been used for more than 50 years, they require intensive coagulation monitoring, are characterised by wide variation in dose-response relationships, and have been associated with multiple drug-food and drug-drug interactions [7,8] . DOAC were recently introduced into clinical practice with the aim to overcome some of the limitations of VKA; however, some DOAC present narrow therapeutic windows, a factor that contributes to reduce adherence rates [8].
Brazilian Journal of Cardiovascular Surgery The questionnaires were applied from September 2019 to January 2020. Pharmacists were interviewed using an electronic form, while the general population was interviewed under the supervision of an interviewer; both groups were asked to respond based on their knowledge on anticoagulation. For the patient group, the questionnaires were applied in a tertiary hospital in the South Region of Brazil (Curitiba, Paraná) using the printed version of the AKT-Br and under the supervision of an interviewer.

Statistical Analysis
The original 28-item structure of the AKT was maintained for all analyses [14] . Descriptive statistical analyses were performed to describe the characteristics of the sample. The variables age, treatment, gender, and educational level were considered non-normally distributed. The results are presented as relative and absolute frequencies for categorical variables and as the median and the interquartile range (IQR) (presented in square brackets) for continuous variables. Contrasted group analysis was conducted to assess differences in the mean scores between the three groups. One-way analysis of variance (ANOVA) with Tukey's post hoc analysis was used to explore statistical differences [23] .
Statistical tests that assess internal consistency and testretest reliability are commonly used in self-administered instruments to ensure the reliability of the instrument [24] . The evaluation of internal consistency was performed through Cronbach's alpha coefficient that uses a scale of 0 to 1, where values close to 0.7 are considered acceptable and values > 0.9 are redundant [25,26] . In addition, for instruments with more than 15 items it is recommended to apply the interitem correlation [27] . The test-test reliability was obtained by reapplying the test to the same group, considering an appropriate time interval (14 days). Reliability coefficients between 0.7 and 0.8 (on a scale of 0 to 1) are considered acceptable [24] . The level of significance of each test was set at 0.05 (two-tailed). All statistical analyses were conducted using RStudio (version 1.3.1073).

Ethics
The research was conducted within the standards required by the Declaration of Helsinki and approved by the Ethics Committee of the Hospital de Clínicas of the Universidade Federal do Paraná (Curitiba, Paraná, Brazil) under registration number CAAE: 16858719.1.0000.0096.

Cultural and Linguistic Validation
The final version of the AKT-Br (see Supplementary Material) was obtained through the consensus discussion of five anticoagulation specialists. Two hundred people were invited to participate in the study (75 pharmacists, 75 patients, and 50 people from the general population), of whom 148 met all eligibility criteria and were included for statistical analyses (55 pharmacists, 57 patients, and 36 people from the general population). Of this sample, 96 were women (64.9%), with a median age of 36 [IQR 28-53] years. About 67% of patients had used OAC for > 2 years (see Table 1).

Quantitative and Qualitative Content Validity
The unilateral ANOVA did not reveal a correlation between the total score and age (F=4.8365; P<0.001), but there were correlations for gender, education, and group (F=10.0121, 11.0706, 172.0956, respectively; P<0.001), where women, individuals with higher education, and pharmacists presented the highest scores.
The evaluated items of the tool presented I-CVIs ranging from 0.7 to 1 and an S-CVI of 0.92 (see Table 2). Cronbach's alpha for the pharmacist and patient groups were 0.71 and 0.65, respectively. The test-retest reliability resulted in r=0.99 (P<0.001). The textual analysis showed that the AKT-Br presents clear and relevant items, without the need for further modifications.

DISCUSSION
We developed and validated the AKT-Br and obtained supporting evidence for validity and reliability. We showed the instrument is useful in a non-English setting to objectively assess patients' knowledge on anticoagulation.
The relationship among patients' knowledge and adherence to OAC has been discussed for more than 30 years [9] , with important impacts on patients' clinical and economic outcomes [12,28,29] . Deshpande et al. [30] showed a significant reduction in the total adjusted costs of treatment of $29,742 for adherent patients vs. $33.609 for non-adherent patients. Although the costs with medication were higher in adherent patients ($5,595 vs. $2,233), these were offset by the reduction in the medical costs ($23,544 vs. $30,485), which may include readmissions or hospitalisations. Fonseca et al. [31] demonstrated that the average length of hospital stay of patients using dabigatran or warfarin is around 4.8 and 5.5 days, with costs of $9,803 and $9,755, respectively.
These figures highlight the key role of patients' selfmonitoring and the use of healthcare interventions/services. In this context, Obamiro et al. [14] developed the AKT to provide an instrument capable of assessing a patient's knowledge regarding her/his anticoagulant treatment, where, according to the score obtained by the patient, health professionals could carry out patients were as follows: incomplete questionnaire completion and OAC treatment duration < 3 months. For illiterate patients or those with reading difficulties, the questions and answers options were read by the interviewers exactly as written, minimising possible bias, while for the others the questionnaires were self-administered [22] .
Brazilian Journal of Cardiovascular Surgery The availability of this tool in other languages besides English -such as Italian, as previously validated by Magon et al. [32] , or in Brazilian Portuguese -also allowed us to standardise how the results are presented and to further compare data among populations of different countries. In Brazil, several tools that have been translated into Portuguese and validated are now available in clinical practice. Examples include the Morisky Medication Adherence Scale [33] -an eight-item tool that assesses the therapeutic adherence of patients undergoing treatment for hypertensionand the Diabetes Quality of Life Measure [34] -a 46-question instrument that evaluates the quality of life of type II diabetes patients. assertive and personalised educational interventions towards better outcomes. In addition, researchers can use the AKT to measure the potential benefits of different interventions in patients using OACs [32] .
Brazilian Journal of Cardiovascular Surgery Brazilian Journal of Cardiovascular Surgery

Item 15
Would you inform a surgeon, dentist or other health professional that you are taking this medicine before undergoing surgery or a procedure? (Você informaria um cirurgião, dentista ou outro profissional de saúde de que está tomando esse medicamento antes de realizar uma cirurgia ou um procedimento?) 1 1 1

Item 16
Is it important that all the health care practitioners you see know that you are taking this medicine? (É importante que todos os profissionais de saúde pelos quais você é acompanhado saibam que você faz uso de anticoagulante?) Brazilian Journal of Cardiovascular Surgery validity of the tool. In addition, some educational limitations from the population led the interviewer to assist in the interpretation of the questions, a factor that may generate bias. In addition, 90% (n=50) of the evaluated patients were warfarin users. This may imply a possible selection bias, which is compatible with the convenience sampling or a need to a readdress the management strategy of Brazilian patients prescribed OAC. This factor may also limit the assessment of data from patients only using DOAC.
The main objective of the study was to validate the AKT-Br as a psychometric analysis tool. However, clinicians can also benefit from the development of a "scale of knowledge" according to the obtained scores. For example, to minimise adherence issues and OAC adverse events, patients who score between five and 10 points (out of 35) probably need to receive different educational interventions compared to those who score 20-25 points. This is especially important in regions or countries with greater socioeconomic inequalities.

CONCLUSION
We showed that the developed AKT-Br is a valid psychometric tool for Brazilian Portuguese. This tool may enhance the quality of life and care of patients using OAC by minimising adverse effects and improving adherence to treatment through tailored educational interventions. Thus, we strongly recommend its routine use in clinical practice. Assessing the knowledge of DOAC users should be better addressed in the future.
An instrument's validity is not limited to a measurement of its properties; it is also an interaction of the scale with the population being tested. The results, when represented by numbers, allow researchers to measure specific population phenomena [35] that may vary according to the cultural-linguistic features of that population. In other words, an instrument is not always valid or applicable from one population to another, or from another language compared with the original. That is why the challenges related to tool validity in cross-cultural research are mainly due to content validity. A tool is valid when the content, criteria, and construct validity items are minimally met. Content validity reflects the degree of adequacy of the instrument that is being built in relation to the study population. This occurs through the discussion of expert panels (3-5 specialists) and qualitative approaches that measure the CVI [19,20,24,36] , as performed in our study.
Construct validity is assessed through hypothetical predictions usually supported by hypothesis tests using a group contrast approach [23] . Different results are expected in the evaluated groups, an outcome that allows researchers to confirm the capacity of the instrument to detect differences in the population [20,36] . This comparison among groups is not intended for clinical implications; it is only meant to assess validity. We validated the AKT-Br construct according to Terwee's recommendations [37] . Unidirectional ANOVA and Tukey's post hoc analysis demonstrated a significantly higher level of knowledge in the pharmacist group compared with the patient group and in the patient group compared with the general population. These results are in accordance with the findings of Obamiro et al. [14] and Magon et al. [32] , who, in addition to expecting a higher score from the pharmacist group (specialists), presented significant differences among all group comparisons. These data strengthen the theory of the group comparison method for construct validity [23] , where the different levels of knowledge about anticoagulation could be stratified, validating the contractor's ability to distinguish them. Finally, the AKT-Br presented a positive and significant correlation coefficient in the test-retest analysis, reaffirming the stability and reliability of the instrument at different times of application. This implies that the tool can be useful to provide consistent scores over time in a stable group of patients. AKT-Br items are interrelated, measuring the same construct, which is similar to the results obtained in the original research [14] .

Limitations
The results obtained with the AKT-Br tool highlight the validity of its translation and cross-cultural adaptation to Brazilian Portuguese. Nonetheless, our study has some limitations. First, it lacks a criterion validity using a measure of adherence (e.g., Morisky score) and testing a priori framework, where patients with higher adherence should be those with greater knowledge. The data from the group of patients was obtained from a tertiary hospital in Curitiba, Paraná (South Region of Brazil), who may not reflect the cultural features of the entire country nor be representative of the Brazilian population taking OAC. Further analyses can be performed in other regions to guarantee the This study was supported by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior -Brasil (CAPES) -Finance Code 001. The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.  Alguns riscos relacionados ao estudo podem ser referentes ao constrangimento durante a entrevista, oriundos de alguma questão que possa causar-lhe desconforto; nesse caso, o pesquisador coloca-se à disposição para esclarecimentos.